We have utilized a series of murine B16 melanoma variant cell lines which show enhanced ability to colonize lung, brain or ovary in order to study the role of cell-surface components in distant melanoma metastasis to specific organs. We have found that quantitative alterations in certain cell-surface glycoproteins correlate with metastasis to specific sites. For example, the presence of gp90 (a 90,000 molecular weight glycoprotein) on the surfaces of brain-colonizing B16 cells correlates with metastasis to brain meninges in cell clones and cell lines selected for meningeal metastasis. We have isolated gp90 and have made antibodies against this component. The antibodies have been used to localize micrometastases in sections of brain and to determine the normal tissue distribution of cross-reacting antigens. In this case, we have found gp90-like molecules in fetal melanocytes located in the developing eye, suggesting that gp90 is a fetal antigen which may be involved in organ targeting by melanoma cells. In other studies we have examined the role of enzymes in breachment of the endothelial basal lamina. We developed an invasion assay utilizing vascular endothelial cell monolayers to study metastatic tumor cell interactions and have found that highly metastatic melanoma cells adhere at high rates to subendothelial basal laminalike matrix and utilize enzymes to degrade the structure. We have concentrated on the enzymes involved in destruction of proteoglycans of the matrix and have identified a unique endo-betaglucuronidase (heparanase) which cleaves heparan sulfate side chains of the major matrix proteoglycans. We have found that the activity of this enzyme correlates with metastatic potential better than tumor cell proteases. We, therefore, established an extremely accurate assay based upon the ability of metastatic cells to degrade purified heparan sulfate. We have found that this assay may be useful in detecting a variety of metastatic tumor cells.